Red blood cells are essential for transporting oxygen throughout the body. Red blood cells are made up of hemoglobin, which is a multi-subunit oxygen-transport metalloprotein. During development, embryonic hemoglobin is composed of epsilon chains (encoded by HBE1) and zeta chains and is produced by the embryonic yolk sac. In human infants, hemoglobin is made up of alpha chains (encoded by HBA1 and HBA2) and gamma chains (encoded by HBG1 and HBG2), with the gamma chains gradually replaced by beta chains over time. The majority of hemoglobin in adults is made up of alpha chains and beta chains (encoded by HBB) with a small percentage (about 3%) made up of alpha and delta chains (encoded by HBD). Several disorders are caused by mutations in hemoglobin subunits and affect red blood cell function or production, resulting in anemia. Two major diseases that affect red blood cells include sickle cell anemia and thalassemia.
Sickle cell anemia is a recessive disorder caused by the absence of a polar amino acid at position six of the beta-globin chain due to a point mutation in HBB. The absence of this amino acid causes aggregation of hemoglobin and results in red blood cells having a stiff, sickle shape. The rigidity of these red blood cells results in vessel occlusion and ischaemia as the cells pass through capillary beds. Anemia is also a symptom, due to the excessive lysis of sickle-shaped red blood cells. Mouse models of sickle cell anemia have shown that expression of other hemoglobin subunits can alleviate symptoms. In adult sickle cell anemia mice, for example, expression of HBE1, which is normally not expressed in adults but serves a similar function as beta-chains during embryonic development, restores the mice to a normal phenotype.
Thalassemia is a group of hereditary blood disorders characterized by a reduced amount of hemoglobin and fewer red blood cells. There are several types of thalassemia, including alpha-thalassemia, beta-thalassemia, delta thalassemia. Alpha-thalassemia is caused by mutations in the HBA1 or HBA2 gene. These mutations cause reduction in alpha-globin production and formation of beta-chain tetramers with altered oxygen profiles and anemia. Delta-thalassemia is caused by a reduction in the synthesis of delta chains of hemoglobin, which is encoded by HBD. Beta-thalassemia, the most severe form of thalassemia, is caused by a reduction in the synthesis of the beta chains of hemoglobin, which is encoded by HBB. Beta-thalassemia is classified into three types, thalassemia minor, thalassemia intermedia, and thalassemia major, depending on the number of mutations and disease severity. Thalassemia minor occurs when only one beta globin allele is mutated and results in microcytic anemia. When more than one allele is mutated, thalassemia intermedia or thalassemia major can occur depending on the severity of the mutation. Patients with thalassemia major require blood transfusions or bone marrow transplantation, otherwise anemia, splenomegaly, and severe bone deformities occur. Patients with thalassemia intermedia may require blood transfusions depending on the severity of the disease.